Open access peer-reviewed chapter

The Expanding Role of Pyridine Derivatives as Privileged Scaffolds in Cardiac Ionic Channels

Written By

Yasodha Krishna Janapati, Sunithasree Cheweti, Bojjibabu Chidipi, Medidi Srinivas and Sunil Junapudi

Submitted: 18 June 2022 Reviewed: 26 July 2022 Published: 07 November 2022

DOI: 10.5772/intechopen.106759

From the Edited Volume

Exploring Chemistry with Pyridine Derivatives

Edited by Satyanarayan Pal

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Abstract

Pyridine-based ring systems are heterocycle-structured subunits that are being abundantly employed in drug design, primarily because of their tremendous effect on pharmacological activity, which has resulted in the discovery of various broad-spectrum medicinal compounds. Pyridine derivatives are employed to treat multiple medical illnesses, including prostate cancer, AIDS, tuberculosis, angina, ulcer, arthritis, urinary tract analgesic, Alzheimer’s disease, and cardiovascular diseases. This chapter emphasized the currently available synthetic pyridine derivatives, including nimodipine, ciclopirox, efonidipine, nifedipine, milrinone, and amrinone, effects on cardiac ionic channels and their mechanisms of action for the cure. Pyridine derivatives regulate several voltage-gated ion channel behaviors, including sodium (Nav), calcium (Cav), and potassium (Kv) channels, and are set as a therapeutic approach. Particularly, calcium-channel blockers are the most common action of medicines with a dihydropyridine ring and are often used to treat hypertension and heart-related problems. Finally, this chapter gives the prospects of highly potent bioactive molecules to emphasize the advantages of using pyridine and dihydropyridine in drug design. This chapter discusses pyridine derivatives acting on cardiac ionic channels to combat CVS diseases. The book chapter describes the importance of pyridine derivatives as a novel class of medications for treating cardiovascular disorders.

Keywords

  • pyridine derivatives
  • privileged
  • scaffolds
  • cardiac ions

1. Introduction

1.1 The physiological role of Pyridine derivatives

Heterocycles are vital in the pharmaceutical sectors, which are an integral part of the essential roof of life processes, that is, DNA and RNA [1, 2, 3]. Recently, 90% of newly produced and commercialized medicines integrate heterocyclic compounds [4]. Pyridine and dihydropyridine are 6-membered heterocyclic rings with a wide variety of therapeutic potential in cardiovascular diseases, ulcers, HIV, antibacterial activity, etc. [5, 6, 7, 8, 9]. Pyridines are typically found in plants with the alkaloids, such as nicotine, anabasine, and trigonelline [10]. In the biochemical process, nicotinamide adenine dinucleotide (NAD) redox reactions are reduced to NADH, and a dihydropyridine ring is present in NAHD. We can also notice dihydropyridine ring in NADPH structure which reduced from the NADP+ [11]. The food and drug administration (FDA) has approved 14% of drugs containing pyridine and dihydropyridine scaffolds [10].

1.2 Natural and commercial drugs with pyridine and dihydropyridine scaffolds

Pyridine and dihydropyridine are versatile chemicals used to make libraries with various functional groups and therapeutic objectives. The existence of pyridine or dihydropyridine heterocycles significantly impacts pharmacological properties. For instance, the pyridine ring in a medication boosts physiological properties, potency, metabolic stability, permeability, and binding to the protein [12]. There is a myriad of commercially accessible medications that include pyridine rings on the market which we listed in the below table.

Name of drugsDiseaseReferences
Pyridine derivative
AbirateroneProstate cancer[13]
DelavirdineAntiviral against HIV/ AIDS[14]
DoxylamineAllergies[15]
EnpirolineMalaria[16]
IsoniazidTuberculosis[17]
NicotinamidePellagra[18]
NikethamideRespiratory stimulant[19]
OmeprazoleUlcers[20]
PiroxicamArthritis[21]
PyridostigmineMyasthenia gravis[22]
TacrineAlzheimer’s[23]
TropicamideAntimuscarinics[24]
NicorandilVasodilator[25]
MetyraponeNSAID[26]
BromazepamAnxiety[27]
EtoricoxibNSAID[28]
TenoxicamRheumatoid arthritis and osteoarthritis[29]
Droxicam[30]
AmpiroxicamAnti-inflammatory[31]
Lornoxicamrheumatoid arthritis[32]
ClonixinArthritis, migraine, and tissue disorders[33]
PhenazopyridineUrinary tract infections and analgesic activity[34]
PitavastatinLowering cholesterol[35]
Ceftaroline fosamil, tedizolid, ceftazidime, delafloxacinAntibiotic[36, 37, 38, 39]
EthionamideTuberculosis[40]
Nevirapine, tipranavir, indinavirHIV/AID[41, 42]
Axitinib, sorafenib, regorafenib, alpelisibCancer treatment[43, 44, 45, 46, 47]
Lorlatinib, acalabrutinibLung cancer[48, 49]
Abemaciclib, neratinibBreast cancer[50, 51]
Nedocromilcure allergic conjunctivitis[52]
BetahistineMénière’s disease[53]
AmifampridineLambert-Eaton myasthenic syndrome (LEMS)[54]
Chlorpheniramineantihistaminic[55]
PyridoxineDeficiency of vitamin B6 and peripheral neuritis[56]
AmlexanoxAsthma and Rhinitis[57]
CarbinoxamineRhinitis and vasomotor rhinitis[58]
DoxylamineAllergies[59]
BrompheniramineCough, and Nasal congestion[60]
NedocromilAllergic conjunctivitis[61]
NedocromilAllergic conjunctivitis[61]
RupatadineAllergic rhinitis[62]
AcrivastineRhinitis[63]
IndacaterolAsthma[64]
TriprolidineAntihistamine[65]
BepotastineItching[66]
NiacinPellagra and Hypertriglyceridemia[67]
PyrithionDandruff and Seborrheic Dermatitis[68]
NicotineSymptoms of nicotine and Smoking cessation[69]
Lemborexant, zolpidemInsomnia[70, 71, 72]
Quinine, chloroquineMalaria[73, 74]
DiiodohydroxyquinolineAmebiasis[75]
TelithromycinPneumonia[76]
TrovafloxacinChlamydia, and Gonorrhea[77, 78]
ImiquimodWarts[79]
UbrogepantMigraine[52]
Chromium picolinateRegulation of insulin function[80]
Chromium nicotinateChromium deficiency[81]
Dihydropyridine ring–containing drug
CiclopiroxRingworm and athlete's foot[82]
DoravirineHIV/AIDS[83]
NADHnutraceutical[84]
CabotegravirHIV1[85]
Huperzine aAlzheimer's disease[86]
Nifedipine pyridine and dihydropyridine ring systemsRaynaud's syndrome[87]
Milrinone and amrinoneVasodilators[88, 89]

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2. Pyridine and dihydropyridine scaffolds with cardiovascular action

Torsemide with pyridine is an approved medicine that stimulates diuresis and reduces the patient’s blood pressure [90]. Most dihydropyridine rings act as calcium-channel blockers, most commonly used to treat high blood pressure and cardiovascular disorders [91, 92]. The dihydropyridine ring-containing drugs are nilvadipine, nifedipine, amlodipine, azelnidipine, clevidipine, and felodipine [10]. Nimodipine helps cure vasospasm and subarachnoid hemorrhage [93, 94]. Levamlodipine, isradipine, nicardipine, benidipine, felodipine, nisoldipine, nitrendipine, and clevidipine are used to treat hypertension [95, 96, 97, 98, 99, 100, 101, 102]. Efonidipine is specially used to treat hypertension and angina [103]. Torasemide is also a cure for renal and liver diseases other than heart failure and hypertension [104]. Quinidine is used to treat atrial fibrillation and flutter [105]. Papaverine used as vasodilator [106].

The nifedipine drug is also used to treat diseases premature birth and Raynaud’s syndrome [87]. Milrinone and amrinone are FDA-approved vasodilators containing pyridine and dihydropyridine ring systems [88, 89].

Examples of a few pyridines and dihydropyridine derivatives of cardiovascular action drugs are shown in Figure 1.

Figure 1.

Pyridine and dihydropyridine derivatives of cardiovascular action drugs.

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3. Pyridine derivatives regulation of cardiac ion channel behaviors is established as a therapeutic strategy

3.1 Cardiac ion channels

Ion channels are pore-forming membrane proteins that permit ions to pass through the channels. The selective permeability of ion channels on the cell membrane causes the heart to produce an action potential. The ion channels reduce the activation energy required for ion movement across the lipophilic cell membrane. Ion channels are established within the membrane of all excitable cells and various intracellular organelles. In search for new drugs, ion channels are a recurrent target [107].

All elements of cardiac function, including rhythmicity and contractility, rely on ion channels. Ion channels are unavoidably important therapeutic targets for heart pathology, such as atrial fibrillation or angina [108].

3.2 Cardiac action potential and ion channels

The cardiac action potential is characterized by a rapid shift in membrane potential (voltage) across the cell membrane of heart cells. The passage of ions between the interior and exterior of cells via proteins known as ion channels generates the cardiac action potential [109]. Ion channels have unique structures and are composed of numerous proteins situated in the cell membrane [107]. Identifying the ion channels that create the action potential is accomplished by examining the molecular basis of hereditary cardiac arrhythmias.

Normal atrioventricular and ventricle contraction requires the fast stimulation or activation of cardiac cell clusters. An activation mechanism must authorize rapid heart rate variations and respond to changes in autonomic tone. These responsibilities are executed by generating the cardiac action potential [107]. The five phases of the cardiac action potential are depicted in Figure 2 [107]:

  1. In healthy functioning cardiac cells, phase 4 (resting potential) is around −90 mV.

  2. Phase 0 is known as the rapid depolarization phase. The membrane potential shifts toward the charge. This phase is central to the rapid cardiac impulse propagation (conduction velocity, θ = 1 m/s).

  3. Phase 1 is characterized by fast repolarization. This phase of the action potential establishes the potential for phase 2.

  4. The most prolonged phase is phase 2, a plateau phase. It distinguishes excitable cells and indicates the time of calcium entry into the cell.

  5. Phase 3 is the rapid repolarization phase, during which the membrane potential is restored to its resting value [110].

Figure 2.

Membrane currents that provide a standard action potential.

The five phases of the action potential are resting (4), upstroke (0), early repolarization (1), plateau (2), and final repolarization. A broken line represents a fall in potential toward the end of phase 3 in pacemaker cells, such as the sinus node. The inward currents INa, ICa, and the sodium-calcium exchanger are illustrated in yellow boxes (NCX). It is electrogenic and can produce both inward and outward currents. Gray boxes represent IKAch, IK1, Ito, IKur, IKr, and IKs. The action potential duration (APD) is typically between 200 and 400 milliseconds [111].

The start of the action potential and the variances observed throughout the heart show that ion channels dispersed on the cell membrane have selective permeability. Ion channels minimize the activation energy required for ion transport across the lipophilic cell membrane [107].

Ion channels have two primary characteristics: ion permeation and gating [112]. The passage of ions via an open channel is described by ion permeation. The classification of ion channels is based on the selective permeability of ion channels to specific ions (e.g., Na+, K+, and Ca2+ channels). Size, valency, and hydration energy are essential factors of selectivity. Ion channels do not function as simple fluid-filled pores but provide multiple binding sites for ions as they traverse the membrane. Most ion channels are singly occupied during permeation; specific K+ channels may be multiply occupied. The bulk of ion channels has a nonlinear current–voltage relationship. The size of the current depends on the direction of ion migration into or out of the cells for the same absolute degree of change in voltage. This is known as rectification, an essential trait of K+ channels; they carry minimal outward current at positive (depolarized) potentials. The fundamental mechanism of rectification differs depending on the kind of ion channel. The mechanism of significant inward rectification displayed by many K+ channels is blocked by the internal Mg+ and polyvalent cations [113].

Ion channel gating, which explains how they open and close, is their second characteristic. Ion channels can also be categorized into categories based on their gating mechanisms, including voltage-dependent, ligand-dependent, and mechano-sensitive gating. Voltage-gated ion channels modify their conductance in response to variations in membrane potential. The gating mechanism used by ion channels is typically voltage-dependent [109].

Changes in the electrical membrane potential close to the channel cause a set of transmembrane proteins called voltage-gated ion channels to open and close. The channel proteins’ shape is altered by the membrane potential, which also regulates how they open and close. Ions must diffuse through the membrane through transmembrane protein channels because they are unable to generally flow through cell membranes. They are essential for enabling an immediate and coordinated depolarization in response to triggering voltage changes in excitable tissues, such as neurons and muscle cells [114]. The opening and closing of the channels are activated by changing ion concentration, and hence charge gradient between the sides of the cell membrane [115].

3.3 Voltage-gated sodium (Nav)

Nav channels are integral membrane proteins that change conformation in response to membrane potential depolarization, open a transmembrane pore, and convey sodium ions inward to initiate and propagate action potentials. Nav is responsible for the rising phase of action potentials in excitable cells, such as neurons, myocytes, and certain types of glia. These channels cycle through three states: resting, active, and inactive. Even though the ions would not be able to move through the channels in their resting or inactive states, there is a variation in their structural conformation. When the membrane potential of a cell change, a modest but noteworthy number of Na+ ions migrate into the cell down their electrochemical gradient, further depolarizing the cell. Therefore, the more the Na+ channels get localized in a section of a cell’s membrane, the more excitable and quickly propagating the action potential of that portion of the cell will be [116].

3.4 Voltage-gated calcium (Cav)

There are two voltage-gated Cav channels within the cardiac muscle: L-type calcium channels (“L” for Long-lasting) and T-type calcium channels (“T” for Transient, i.e., short). L-type channels are more numerous and densely populated within ventricular cell t-tubule membranes. On the other hand, T-type channels are located primarily within atrial and pacemaker cells but to a smaller extent than L-type channels. Higher positive membrane potentials activate L-type channels, take longer to open, and remain open for a longer time than T-type channels. This implies that T-type channels contribute more to depolarization (phase 0), whereas L-type channels contribute more to plateauing (phase 2) [117].

3.5 Voltage-gated potassium (Kv)

Kv is the most widely distributed ion channel type found in all living organisms. They are transmembrane channels specific for potassium and sensitive to voltage changes in the cell’s membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting stage. Potassium channels are found in most cell types and control various cell functions [112].

The two main K+ channels in cardiac cells are inward rectifiers and voltage-gated potassium channels.

Potassium channels that internally correct (Kir) encourage the entry of K+ into cells. However, the significance of this potassium influx increases when the membrane potential is lower than the equilibrium potential for K+ (~ − 90 mV). The amount of potassium entering the cell through the Kir reduces as the membrane potential moves in a more positive direction, as it does when an adjacent cell stimulates the current flow. Kir is therefore in charge of preserving the resting membrane potential and starting the depolarization phase. However, the channel starts to let K+ leave the cell when the membrane potential continues to move in a more positive direction. The Kir can also help with the last phases of the repolarization because of this outward influx of potassium ions at the more positive membrane potentials [118].

Depolarization activates voltage-gated Kv channels. These channels generate currents, such as the transient out potassium current Ito1. This current is made up of two parts. Both components activate quickly. However, Ito, fast deactivates faster than Ito, slow. These currents contribute to the action potential’s early repolarization phase (phase 1) [118].

The delayed rectifier potassium channels are yet another variety of voltage-gated potassium channels. These channels transport potassium currents that cause the action potential’s plateau phase. They are named according to how quickly they activate: IKs that activate slowly, IKr that activate quickly, and IKur that activate extremely quickly [119].

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4. Pyridine derivatives an ion channels modulator

The pyridine ring system can be found in a variety of natural products and pharmaceutically relevant molecules. Many of these compounds have fascinating and distinctive pharmacological characteristics that have often encouraged their production and reactivity. This chapter highlights recent advances in the regulation of several ion channel behaviors, such as voltage-gated sodium (Nav), calcium (Cav), and potassium (Kv) channels by the Pyridine derivatives [120].

4.1 Regulation of voltage-gated calcium (Cav) ion channel by pyridine derivatives

Calcium channel blockers (CCBs) are unique drugs that prevent calcium from moving through calcium channels. They all have a similar mode of action, but are not interchangeable and can have diverse physiologic consequences. Calcium channel blockers are divided into dihydropyridines [DHPs] such as nifedipine and non-DHPs such as verapamil and diltiazem. These families bind to calcium channels at various binding locations, which could explain the clinical discrepancies. Non-dihydropyridines are more myocardial selective and tend to lower the heart rate, while dihydropyridines are more vascular selective [121]. Calcium channel blockers all relax atrial smooth muscle and cause peripheral vasodilation, decreasing blood pressure.

Furthermore, because calcium is directly implicated in cardiac contraction, lowering intracellular calcium concentrations via calcium channel blocking can reduce ventricular contractility. However, DHP CCBs do not exhibit this negative ionotropic effect, since they are more effective peripheral vasodilators than verapamil and diltiazem [122]. Because of their cardiac inotropic and vasomotor properties, DHPs are frequently employed as medicines. Many members of this class are commercially important cardio protectants, vasodilators, and calcium antagonists [123]. This possible peripheral vasodilation causes a baroreceptor-mediated increase in sympathetic tone, which mitigates the DHPs’ negative inotropic action. In patients with heart failure and systolic dysfunction, it is recommended to avoid and use calcium channel blockers [non-dihydropyridines] with negative inotropic effects with caution [124]. Verapamil and diltiazem, unlike DHPs, lower the sinoatrial (SA) node conduction rate (negative chronotropes) and slow atrioventricular (AV) conduction (negative chromotropes) [125]. The rationale for employing non-DHPS (verapamil and diltiazem) for the treatment of supraventricular tachyarrhythmias (SVTS) and atrial fibrillation is to slow the rate of conduction via the AV node [126]. The DHP CCBs do not slow conduction across the AV node and are thus ineffective in treating SVT.

Furthermore, they do not disable the SA node’s automaticity. Indeed, DHP CCBs may cause a rise in heart rate due to reflex tachycardia induced by powerful peripheral vasodilation. This effect is particularly noticeable with nifedipine quick release [127]. To emphasize immediate release, when used for acute blood pressure lowering, nifedipine has been linked to increased morbidity (myocardial ischemia and infarction), particularly in individuals with coronary artery disease (CAD) [125]. When taken for acute blood pressure reduction, immediate-release nifedipine has been linked to higher morbidity (myocardial ischemia and infarction), particularly in individuals with CAD [128]. Nifedipine was the chosen drug for hypertension crises because of its quick onset of action.

On the other hand, immediate-release nifedipine is no longer considered safe or efficacious for this indication. Sustained-release nifedipine formulations are less dangerous and do not cause strong reflex reactions to tachycardia. It is also worth noting that reflex tachycardia is not concerned with DHP CCBs with a delayed onset of action, such as amlodipine and felodipine.

To summarize, there are numerous distinctions between DHP and non-DHP CCBs. The non-DHPs are notable for being negative chronotropes, inotropes, and dromotropes. They should be taken with caution in individuals with heart failure and with drugs that have comparable hemodynamic effects. DHP CCBs are the most commonly used medications in individuals with hypertension and angina because they affect cardiac conduction [129].

4.2 Regulation of voltage-gated sodium (Nav) ion channel behaviors by pyridine derivatives

Action potentials are initiated by voltage-gated sodium channels in neurons, cardiac muscle, and other electrically excitable cells. Sodium channel blockers are utilized in local anesthetic and in treating epilepsy, bipolar disorder, chronic pain, and cardiac arrhythmia. Pyridine, having the chemical formula C5H5N, is an essential heterocyclic organic molecule. The presence of a pyridine derivative, such as nicotinamide, as a nitrogen base distinguishes pyridine nucleotides (PNs). In addition to their role as soluble electron carriers, pyridine nucleotides [NAD(P)(H)] influence ion transport mechanisms. According to new research, pyridine nucleotides [NAD(P)(H)] influence ion transport processes in addition to their role as soluble electron carriers. PNs are vital in various physiological responses, including stress, energy metabolism, and cell survival/death in cardiovascular cells. The development of congestive heart failure may be influenced by oxidative stress in the myocardium (HF) [130]. Cells include an antioxidant system comprising GSH and thioredoxin (Trx) and reducing enzymes, such as superoxide dismutase and catalase, to protect against excessive ROS [131]. PNs function in regulating cellular redox status by acting as electron donors for both negative and positive oxidative stress regulators. Pyridine nucleotide regulation of ion channels may be essential for integrating cell ion transport to energetics and sensing oxygen levels or metabolite availability. Aside from these regulatory activities, current research has demonstrated that pyridine nucleotides also influence the activity of ion channels by acting as ligands or substrates of accessory subunits that modify channel gating. The modulation of KNa/SLO2 channels by NAD(P)+ shows that their activity may be linked to the cell’s metabolic condition. This form of control may be especially relevant during ischemia–reperfusion, and other circumstances in which NAD(P)+ buildup may promote K+ efflux through these channels. High intracellular NAD(P)+ levels would also increase the sensitivity of these channels to intracellular sodium [132].

Moreover, it has been proposed that in ischemic cardiac myocytes, increased [Na+]i levels activate KNa, and an increase in this current shortens ADP and promotes calcium overload [133, 134]. As a result, regulating these channels with pyridine nucleotides would allow them to adapt to both the metabolic and ionic circumstances present in the ischemic heart. Interestingly, despite the lack of direct proof, it has been claimed that SLO2 channels exist in the cardiac mitochondria [135]. Pyridine nucleotide control of these channels could present the preservation of the relationship between metabolism and ion transport in modern mitochondria and their prokaryotic progenitors. Although these findings are exciting, more research is needed to understand how intracellular changes in pyridine nucleotides influence SLO channels’ activity and physiological relevance.

4.3 Regulation of voltage-gated potassium (Kv) ion channel activity by pyridine derivatives

Potassium channels are a diverse and widespread type of ion channel. They primarily regulate the cell’s resting membrane potential and reduce the level of excitement. The current invention relates to novel pyridine and quinoline derivatives, pharmaceutical compositions incorporating them, and their use in treating ion channel disorders, such as potassium channel dysfunction. Potassium (Kv) channels also interact with pyridine nucleotide-binding proteins. These channels are essential in numerous physiological functions. They regulate the membrane potential of excitable cells and affect the shape and frequency of the action potential. These channels are also involved in the regulation of neurotransmitter release and cell volume [136, 137], proliferation, [138] and apoptosis [139]. They are also important in T-cell differentiation, activation, and cytokine generation [140]. These channels’ activity affects baseline and agonist-stimulated vasomotor tone, and the membrane hyperpolarization generated by Kv channel activation governs the vasodilation [141]. Oxygen-sensitive variations in Kv channel activity drive hypoxic pulmonary vasoconstriction in small resistance arteries (HPV) [142, 143]. As a result, aberrant Kv channel activity has been linked to cardiac arrhythmias, pulmonary hypertension, epilepsy, and aberrant immunological responses [141, 144, 145]. The many functions of Kv channels are related to their various structures. The ion-conducting pore of Kv channels is produced by four membrane spanning subunits, assembled in a homotetrameric or heterotetrameric fashion. Twelve distinct Kv channel proteins have been reported so far [146, 146]. Several Kv families’ pore-forming subunits interact in situ with accessory subunits that help channel construction and influence channel function, such as Kv family proteins, that interact with the cytosolic domains of Kv1 and Kv4 channel proteins [148]. Pyridine nucleotide function at the binding location N-type inactivation by NADPH, removal of inactivation by NADP+, and membrane trafficking are the functions of voltage-gated potassium (Kv) ion channels’ ancillary subunit-Kv [149]. Changes in the amount of cofactor binding, which passively replicates the physiological levels of these nucleotides, could modulate the gating of the Kv-Kv assembly. Thus, increased intracellular NAD(P)H levels would promote inactivation, but increased NAD(P) + levels would eliminate inactivation. Membrane voltage may influence catalysis via Kv contact with the cytosolic T1 domain or the C-terminus of Kv channels. The C-terminus of the shaker channel linked to Kv2 is in intimate contact with the Kv active site, according to the electron microscopic single particle analysis [150]. This analysis demonstrates that the Kv channel’s inner helices, which are anticipated to move considerably during gate opening and closing, are directly connected to the channel’s C-terminus. This suggests that the conformation and orientation of the Kv C-terminus relative to the subunits may change as a function of membrane voltage. Kv1.5’s C-terminal peptide interacts more avidly with NADPH than NADP+ bound Kv2, and its deletion prevents differential regulation of Kv1.5 + Kv2 and Kv1.5 + Kv3 currents by reduced and oxidized nucleotides, despite the fact that the role of the Kv C-terminus in enhancing voltage sensitivity to Kv catalysis has not been studied [151]. Despite these observations, the general physiological function of the Kv C-terminus is unknown. The C-terminus of Kv1.1, unlike the C-terminus of Kv1.5, does not affect channel control by Kv1 coupled to pyridine nucleotides [152]. Although pyridine nucleotides have been shown to regulate Kv currents in heterologous systems, the physiological importance of this regulatory axis has yet to be determined. Even though Kv channels are involved in numerous physiological processes, their function is heavily influenced by posttranslational modification and subunit assembly. Pyridine nucleotide regulation may give additional control by linking the activity of these channels to changes in metabolic activity of the cell’s redox state. For example, hypoxic depolarization of pulmonary artery smooth muscle cells (PASMCs), which underpins the HPV phenomenon, has been linked to the Kv1.5 inhibition [153]. The fact that Kv1.5 is oxygen sensitive when produced in PASMCs but not in other cell types suggest that factors other than the pore-forming subunits of the channels may be necessary for the channel’s oxygen sensitivity [154]. The ability of pyridine nucleotide-binding Kv proteins to modulate Kv current might theoretically confer oxygen sensitivity to Kv1.5 channels. Kiβ is abundantly expressed in PASMCs, and its expression is substantially higher in the distal than the proximal bovine pulmonary artery, indicating a potential function in oxygen sensing and HPV infection [155]. Furthermore, the Kv1.5-Kv1.3 channels are the primary components of IKv in PASMC, and these channels are variably controlled by oxidized and reduced pyridine nucleotides in COS-7 cells [153, 155]. As a result, an increase in the NADPH:NADP+ ratio during hypoxia may activate Kv1.5-Kv1.3 currents at more negative membrane potentials, whereas the current is blocked at higher positive membrane potentials, where inactivation becomes more pronounced. This activity has only been observed in hypoxic canine PASMC and not in other species [156]. This species difference could be attributed to variations in Kv expression. While inhibition may be related to Kv2, which does not impact Kv inactivation but shifts the voltage dependence of activation, hypoxia may increase Kv currents, whilst inhibition may be related to Kv2. However, it would be anticipated that a rise in the NADPH:NADP+ ratio would result in a shift in the activation threshold, that is, more hyperpolarizing than depolarizing [147]. Therefore, more research is needed to implicate Kv in HPV and to determine the role of distinct Kv subunits in regulating the oxygen sensitivity of Kv channels.

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5. Clinical approaches of Pyridine derivatives

A glance at the US FDA database reveals that pyridine and dihydropyridine drugs constitute nearly 14% and 4% of N-heterocyclic drugs are approved for the treatment of various diseases.

5.1 Pioglitazone

Pilot research was conducted to compare the effects of pioglitazone on cardiac function and oxidative stress in patients with type II diabetes and insulin resistance undergoing elective percutaneous coronary intervention to placebo [157]. In cardiac insulin resistance, pioglitazone corrects mitochondrial dysfunction [158], PPARgamma activation which is associated with improving cardiovascular risk were observed in many clinical investigations. The change in cardiovascular or metabolic markers and mRNA will be isolated from circulating mononuclear cells to investigate the degree of activation of the immune system, which is another measurement of the atherosclerosis risk [159]. It also have myocardial protection in atherosclerosis and coronary heart disease [160]. Pioglitazone reduces left ventricular mass in people with type II diabetes who have ischemic heart disease [161]. Pioglitazone treatment or physical training alone enhance the hearts in HIV patients with metabolic syndrome. The combination of physical training and pioglitazone treatment results on in reducing insulin resistance and subsequently improving cardiac metabolism, and enhancing heart function in the type II diabetes population with cardiovascular risk [162].

5.2 Niacin

Niacin plays a key role in regulating atherosclerotic plaque inflammation. It has a protective effect on endothelial progenitor cells and microparticles, and it is vigorously used in chronic statin therapy to treat atherosclerotic disease on chronic statin therapy. The effects of niacin on vascular health were assessed using fluorodeoxyglucose-PET/CT and circulating endothelial progenitor cells and microparticles [163]. Niacin reduces the elevation of triglycerides and HDL [164]. Extended-release niacin/laropiprant has a significant effect in patients with the atherosclerotic disease compared to placebo. Dilatation of arterial walls improved in statin therapy assessed by the brachial vasoreactivity [165].

5.3 Nicorandil

Nicorandil is recommended as a second-line treatment for the angina treatment [166]. Still, randomized-controlled trials going on to evaluate the benefit of nicorandil for patients with chronic total occlusion [167]. The treatment of oral nicorandil to reduced cardiac death after coronary revascularization in hemodialysis patients [168].

Nicorandil, a combination of nitrates, is an ATP-sensitive K+ channel activator that reduces infarct size in animal models. Moreover, a prospective and randomized, multicenter study was conducted by the Japan-working groups of acute myocardial infarction for the reduction of necrotic damage by activating K-ATP channel to determine potential use of nicorandil. The treatment of Nicorandil for acute myocardial infarction, reduces myocardial infarct size and improves regional wall motion [169]. The infarct size in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention treated by nicorandil before and after the reperfusion with those standard therapy treated by percutaneous coronary intervention [170].

5.4 Riociguat

Riociguat has been shown pharmacodynamics affects in patients with pulmonary hypertension and heart failure with remodeled ejection fraction [171].

5.5 Vericiguat

Vericiguat (BAY1021189) is currently being developed to treat heart failure, which is a condition where the heart has unable to pump blood throughout the body. Patients with heart failure frequently also have renal impairment, which prevents the kidneys from properly filtering the blood [172]. Many investigators found the pharmacodynamic drug-drug interaction and the safety and tolerability of Isosorbide Mononitrate and Vericiguat in patients with stable coronary artery disease [173]. In Phase III clinical trials, the optimal dose of soluble guanylate cyclase stimulator BAY1021189 per day by orally preserved ejection fraction in the heart failure [174].

5.6 Mangafodipir

Mangafodipir is also known as manganese dipyridoxyl diphosphate, and its lipophile metabolite manganese dipyridoxyl diethylene diamide has a catalytic antioxidants and iron chelators properties. In preclinical studies, these agents reduce injuries induced by oxidative stress in cancer chemotherapy and reperfusion/reoxygenation of ischemic/hypoxic myocardium. The treatment of Mangafodipir, decreased the size of the myocardial infarct by 55% in a in vivo myocardial infarct pig model. Most likely, mangafodipir promotes recovery of downregulated pathways and guards against fatal reperfusion damage [175].

5.7 Tezosentan

Tezosentan has shown efficacy, and safety profile in patients with acute heart failure [176, 177].

Estrogens, dextrothyroxine, nicotinic acid, and clofibrate are used to treat coronary artery disease. These drugs cause more toxicity [178].

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6. Conclusion

The book chapter describes the importance of pyridine derivatives as a novel class of medications for treating cardiovascular disorders. Pyridine derivatives are known to be ion channel modulators and change the action potential by changing voltage-gated potassium, sodium, and calcium ion channel activity. This chapter presents a critical study of many medications and research on designing and developing various pyridine and dihydropyridine-based derivatives. They have been classified based on their pharmacological activity. Every specific structural aspect relevant to exclusive activities has also been considered. The central pyridine core is more significantly tractable for producing anti-infectious and anticancer medicines. Dihydropyridine derivatives primarily regulate the dihydropyridine protein, also known as calcium channels. Dihydropyridine ring-containing drugs, including nimodipine, ciclopirox, efonidipine, nifedipine, milrinone, and amrinone, primarily function as calcium channel blockers, and are used to treat hypertension and heart issues.

The structure, application, and diversity of pyridine- and dihydropyridine-containing compounds will expand in the future decade, with tremendous potential for new cardiovascular, anti-inflammatory, anti-infectious, neurogenic, and anticancer therapies incorporating the two heterocycles. Because of the enormous structural diversity of pyridine- and dihydropyridine-containing compounds, the present literature just scratches the surface of potential therapeutic applications. In conclusion, paired with a broader chemical space, pyridine and dihydropyridine-containing compounds will aid medicinal chemists in designing bioactive molecules for specific targets.

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Written By

Yasodha Krishna Janapati, Sunithasree Cheweti, Bojjibabu Chidipi, Medidi Srinivas and Sunil Junapudi

Submitted: 18 June 2022 Reviewed: 26 July 2022 Published: 07 November 2022